HES5

Chr 1

hes family bHLH transcription factor 5

Also known as: bHLHb38

NCBI Gene: 388585 ENSG00000197921 UniProt: Q5TA89

The protein is a basic helix-loop-helix transcriptional repressor that functions downstream of the Notch pathway to regulate cell differentiation and acts as a negative regulator of neurogenesis. Mutations in HES5 cause autosomal dominant epilepsy with auditory features. This condition follows an autosomal dominant inheritance pattern and primarily affects the nervous system with seizures and hearing-related symptoms.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of a family of basic helix-loop-helix transcriptional repressors. The protein product of this gene, which is activated downstream of the Notch pathway, regulates cell differentiation in multiple tissues. Disruptions in the normal expression of this gene have been associated with developmental diseases and cancer. [provided by RefSeq, Dec 2008]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.34

Clinical Summary— HES5

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

29 VUS of 31 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.249

Z-score 1.20

OE 0.30 (0.10–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.59Z-score

OE missense 1.27 (1.01–1.61)

49 obs / 38.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.30 (0.10–1.34)

0≤0.351.4

Missense OE?1.27 (1.01–1.61)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 1 / 3.4Missense obs/exp: 49 / 38.6Syn Z: -0.55

This gene — mechanism propensity

0.6355th %ile

GOF

0.4481th %ile

LOF

0.48top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

31 submitted variants in ClinVar

ClinVar

Classification Summary

VUS29

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	29	0	29
Likely Benign	0	1	1
Benign	0	1	1
Total	29	2	31

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

121 pathogenic / likely-pathogenic (of 139) ClinVar copy-number / structural variants overlap HES5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →